Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
  • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
  • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
  • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C47/00—Compounds having —CHO groups
  • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
  • C07C47/277—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
  • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups

Definitions

• This invention relates to the use of certain chemical compounds possessing valuable pharmaceutical activity, particularly as lipoxygenase inhibitors possessing anti-inflammatory and antiallergic properties. Novel intermediates, used for preparing the active therapeutic agents, also possess valuable therapeutic properties, and are also within the scope of this invention.
• Ger. Offen. 3,011,258 describes the preparation of ⁇ , ⁇ unsaturated ketones of the formula in which R 1 and R 2 are C 1 -C 6 alkyl, napthyl or phenyl, with the phenyl moiety being substituted with F, Cl, Br, C 1 -C 4 alkyl, and C 1 -C 4 lower alkoxy, and R 3 is C 1 -C 4 lower alkyl, benzyl or phenyl, with the benzyl and phenyl moieties being substituted with F, Cl, Br, or C 1 -C 4 alkyl.
• R 1 and R 2 are C 1 -C 6 alkyl, napthyl or phenyl, with the phenyl moiety being substituted with F, Cl, Br, C 1 -C 4 alkyl, and C 1 -C 4 lower alkoxy
• R 3 is C 1 -C 4 lower alkyl, benzyl or phenyl, with the benzyl and
• the present invention is concerned with the therapeutic composition
• the present invention relates to the method of using these compounds as lipoxygenase inhibitors possessing anti-inflammatory and anti-allergic responses.
• Also encompassed within the invention are particularly useful intermediates in the preparation of compounds of Formula I, wherein R 2 is OH. These intermediates are composed of Formula II: wherein Ar, Ar l , X, R, R 1 , n, n', a and b are as defined above;
• heterocyclic rings exemplary of Ar and Ar l contain at least one oxygen, sulfur or nitrogen and include the so-called benzoheterocyclic rings.
• exemplary heterocyclics include furan, thiophene, pyrrole, pyridine, thiazole, piperazine, oxazole, benzofuran, quinoline, indole, benzothiophene, benzoxazole and similar heterocyclic rings as well as the N-oxides of the nitrogen-heterocyclics.
• the preferred heterocyclics are quinoline and indole.
• alkyl groups are preferably lower alkyl which may be straight or branched-chain, and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, hexyl and the like.
• halo atoms in halo and trihalomethyl are Cl, Br, I and preferably F.
• the aryl groups are preferably phenyl or naphthyl.
• the preferred compounds of Formula II are those in which n is 1 or 2, n" is 1 and Z contains 0 to 6 carbon atoms.
• aryl groups i.e., phenyl, the aryl group of arylalkyl, and benzoyl, may be unsubstituted or substituted with one or two substituents such as OH, alkoxy, aryloxy, arylalkyloxy, halogen, alkyl, carboxy, carbalkoxy, carboxamide and similar such groups.
• the present compounds can be prepared by art-recognized procedures from known compounds or readily-preparable intermediates.
• An exemplary general procedure is as follows:
• R 2 is OH
• R 2 is OH
• the reaction of a Grignard reagent with an aldehyde intermediate of suitable carbon content can directly form the corresponding secondary alcohol: the corresponding 2° alcohol.
• z 2 is one carbon less than Z.
• the present compounds form salts with acids when a basic amino function is present and salts with bases when an acid function, i.e., carboxyl, is present. All such salts are useful in the isolation and/or purification of the new products.
• Suitable acids include, for example, hydrochloric, sulfuric, nitric, benzenesulfonic, toluenesulfonic, acetic, malic, tartaric and the like which are pharmaceutically acceptable.
• Basic salts for pharmaceutical use are the Na, K, Ca and Mg salts.
• the compounds of the present invention can be administered to the host in a variety of forms adapted to the chosen route of administration, i.e., orally, intravenously, intramuscularly or subcutaneous,topically or inhalation routes.
• the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
• the active compound may be incorporated with excipients and used in the form of ingestible tablets,-buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of the unit.
• the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound.
• the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
• a binder such as gum tragacanth, acacia, corn starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as corn starch, potato starch, alginic acid and the like
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint,
• tablets, pills, or capsules may be coated with shellac, sugar or both.
• a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
• any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
• the active compound may be incorporated into sustained-release preparations and formulations.
• the active compound may also be administered parenterally or intraperitoneally.
• Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
• Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
• the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
• the allylic alcohols 21-40, and 42 and 44 were prepared by mild reduction of the corresponding keto groups in compounds 1-20, 41, and 43 respectively, by the reaction of sodium borohydride as described.
• the melting points are given in tabular form as follows:
• the compounds of the present invention have potent activity in regulating the formation of lipoxygenease and as such possess therapeutic value in the treatment of inflammatory conditions and allergic responses such as anaphlaxis and asthma.
• Lipoxygenases in mammals have been found in the lung, platelets, and white cells. They are enzymes capable of oxidizing arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) and their stable products hydroxyeicosatetraenoic acids (HETEs). Lipoxygeneases are classified according to the position in the arachidonic acid which is oxygenated. Platelets metabolize arachidonic acid to 12-HETE, while polymorphonuclear leukocytes contain 5 and 15 lipoxygenases. It is known that 12-HETE and 5, 12-diHETE are chemotactic for human neutrophils and eosinophils, and may augment the inflammation process.
• 5-HPETE is known to be a precursor of slow-reacting substance of anaphylaxis (SRS-A).
• SRS-A slow-reacting substance of anaphylaxis
• leukotrienes B, C, and D have been shown to be potent bronchoconstrictors (see, NATURE 288, 484-486 (1980)).
• the following protocol describes an assay to detect inhibitors of the lipoxygenase pathway. Such inhibitors are believed to be capable of modulating the biosynthesis of the leukotrienes, a property believed to be useful in treating asthma and inflammatory disease states.
• a suspension of rat neutrophils in buffer is incubated for 3 minutes at 30°C with [ 14 ]-arachidonic acid (AA) and Calcium Ionophore A23 ' 187.
• Citric acid (2M) is used to quench the reaction.
• the mixture is extracted with chloroform/methanol. The organic layer is washed with dilute acid and an aliquot is transferred to glass tubes and dried.
• the residue is dissolved in a small volume of chloroform and an aliquot is spotted on silica gel TLC sheets, which are developed with an ethyl acetate/isooctane/water/acetic acid solvent system.
• the 5-HETE spots are visualized with iodine, cut out and placed in scintillation vials for counting.
• the amount (p mo l e ) of [ 14 C] -5-HETE in each of the tubes is quantitated by substracting the net pmoles of 5-HETE in the tubes containing buffer alone (blank) from the pmoles of 5-HETE in the tubes containing buffer and cells (control).
• the ability of the test compounds to modulate the activity of this enzyme is determined by a decrease or increase in the net amount of 5-HETE produced.
• Some compounds in this invention also display potent activities in regulating phospholipases and as such possess therapeutic value in the treatment of inflammatory conditions.
• Inflammatory responses to a variety of offending stimuli are promoted by products of arachidonic acid metabolism. These products include leukotrienes (SRS-A), prostaglandins, prostacyclin and its metabolites, and thromboxanes.
• SRS-A leukotrienes
• prostaglandins prostaglandins
• prostacyclin and its metabolites prostaglandins
• thromboxanes No matter what combination of products results from passage of substrate down the branches of this complex cascade, the initial step involves the release of arachidonic acid from phospholipids or from triglycerides containing this long-chain fatty-acid .
• the enzymes catalyzing such release of arachidonic acid are:
• PLC Phospholipase C
• P LA 2 Phospholipase A 2
• the PLC employed in this screen is obtained by aggregation of purified rat platelets in the presence of CaCl 2 and ADP.
• phosphatidylinositol having 3 H-labeled arachidonate residues at R2 is employed as substrate.
• PLC acts by cleaving the phosphate ester bond yielding diglyceride as follows: 3 H-Phosphatidylinosit-tol 3 H-diglyceride Inositol (cont.)
• the assay medium is acidified and extracted with hexane which takes up unreacted substrate and diglvceride.
• the hexane extract is passed over a short silica gel column which retains 99% of the phosphatidylinositol.
• the H-labeled diglyceride is not retained (95% recovery in eluate) and is collected directly in scintillation counting vials.
• the diglyceride is conveniently quantitated by liquid scintillation spectrometry.
• the compounds were tested at 300 uM in a buffer containing 0.06 mM unlabeled phosphatidylcholine ( PC ), 20 - 30 , 000 c p m of 14 C [PC], 150 mM NaCl, 5 mM CaCl 2 and 50 mM Tris(hydroxymethyl) methylaminopropanesulfonic acid buffer, adjusted to pH 9.0 with 1N NaOH.
• the temperature of the buffer is maintained at a temperature of 37°C.
• the reaction was initiated by addition of the enzyme and it was terminated 10 minutes later by addition of 1 ml of 1 N HCl.
• the samples were extracted with 2 ml of isopropyl alcohol and 2 ml of hexane, vortexed and allowed to stand until the phrases separate. Free inositol and some unreacted substrate were taken up in the isopropanol-saturated hexane.
• the hexane phase of the extraction mixture was transferred to a short silica gel column which retained unreacted phosphatidylinositol, but not the 3 H-diglyceride.
• the column effluent was collected directly in scintillation vials. The columns were washed once with additional 2 ml of hexane.
• the radiolabeled diglycerides were quantitated by liquid scintillation spectrometry.
• the PLA 2 employed in this screen is obtained by aggregation of purified rat platelets.
• phosphatidylcholine having 14 C -labeled palmitate residues at Rl and R2 is employed as substrate.
• PLA 2 acts by cleaving the R 2 fatty acid ester bond yielding free fatty acid and lysophosphatidyl choline as follows:
• the assay medium is acidified and extracted with hexane, which takes up unreacted substrate and free fatty acid product.
• the hexane extract is passed over a short silica gel column which retains 99% of the phosphatidyl choline.
• the 14 C-labeled palmitic acid is not retained (90% recovery in eluate) and is collected directly in scintillation counting vials.
• the released palmitic acid is conveniently quantitated by liquid scintillation spectrometry.
• the compounds were tested at 100 uM in a buffer containing 0.3 mM unlabeled phosphatidylcholine (PC), 20 - 30 , 00 0 cpm of 14 C [PC], 100 mM NaCl, 1 mM CaCl 2 and 50 mM Tris-HCL adjusted to pH 7.2 with 1 N NaOH. This resulted in a buffer at pH 7.2 The temperature of the buffer is maintained at a temperature of 37°C. The reaction was initiated by addition of the enzyme and it was terminated 30 minutes later by the addition of 100 ml of 1 N HCL.
• PC unlabeled phosphatidylcholine
• the complex was extracted with 2 ml of 2-propanol and 2 ml of hexane, vortexed, and allowed to stand until the phases separated.
• Free fatty acids (FFA) and some unreacted substrate were taken up in the isopropanol-saturated hexane.
• the hexane phase of the extraction mixture was transferred to a short silica gel column which retained unreacted PC but not the FFA.
• the column effluent was collected directly in scintillation vials. The columns were washed once with an additional 2 ml of hexane.
• the radiolabeled FFA were q uantitated by liquid scintillation spectrometry.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Pulmonology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Quinoline Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)

Applications Claiming Priority (2)

Publications (2)

Family

ID=24779381

Family Applications (1)

Country Status (7)

Cited By (5)

Family Cites Families (3)

• 1986
  • 1986-01-17 EP EP86100592A patent/EP0189142A3/de not_active Withdrawn
  • 1986-01-17 NO NO860170A patent/NO860170L/no unknown
  • 1986-01-17 DK DK22886A patent/DK22886A/da not_active Application Discontinuation
  • 1986-01-17 FI FI860227A patent/FI860227A7/fi not_active IP Right Cessation
  • 1986-01-17 AU AU52594/86A patent/AU5259486A/en not_active Abandoned
  • 1986-01-17 ZA ZA86370A patent/ZA86370B/xx unknown
  • 1986-01-17 JP JP61006589A patent/JPS61172843A/ja active Pending

Also Published As

Similar Documents

Legal Events